Metabolic reactions in response to molecular oxygen can produce harmful reactive oxygen species such as the superoxide ion (O.sub.2.sup.-), hydrogen peroxide or hydroperoxide ion (H.sub.2 O.sub.2 or .sup.- OOH), or hypochlorite ion (ClO.sup.-). For example, reactive oxygen species are produced by uncontrolled activated neutrophils at inflammation sites in the human body. Patients with myocardial ischemia can suffer irreparable tissue damage due to the production of H.sub.2 O.sub.2 or O.sub.2.sup.-. This effect is also found in and may be causally related to rheumatoid arthritis. Reactive oxygen species are also implicated in carcinogenesis.
A number of naturally occurring enzymes aid in the decomposition of harmful reactive oxidants. Superoxide dismutase (SOD) denotes a family of metalloenzymes that catalyze, among other reactions, the dismutation of superoxide ions according to the following equation: EQU 20.sub.2.sup.- +2H.sup.+ .fwdarw.H.sub.2 O.sub.2 +O.sub.2.
The still-harmful SOD reaction product, hydrogen peroxide, is subject to further dismutation by the enzyme catalase according to this equation: EQU 2H.sub.2 O.sub.2 .fwdarw.2H.sub.2 O+O.sub.2.
Thus, SOD and catalase together catalyze the overall dismutation of superoxide to water and oxygen, and form an important part of an organism's self-protective system against reactive oxidants.
Enzymes of the SOD family have many important uses. U.S. Pat. No. 4,029,819 to Michelson teaches the use of SOD as a foodstuff additive and preservative for the prevention of oxidation and auto-oxidation of lipids. U.S. Pat. No. 4,129,644 to Kalopissis et al. teaches the application of SOD to protect skin and maintain the integrity of the natural keratinic structure of skin and hair. The usefulness of SOD in alleviating skin irritation and inflammation is demonstrated in U.S. Pat. No. 4,695,456 to Wilder. SOD may also be used as a general anti-inflammatory, and as an attenuator to be applied after exposure to superoxide ion-generating agents such as radiation or paraquat, as described in European Patent Application No. 84111416.8 to Hallewell et al.
The catalytic activity of SOD and catalase, and many other metabolic enzymes in biological systems, requires the presence of one or more metal ligands at the catalytic site. Covalently linked cofacial- ("strati-") bisporphyrins and their metal complexes have been employed as models for these multimetal proteins. See, e.g., D. Dolphin et al., Heterocycles (1981) 16:417. Extensive studies have been carried out on the four electron reduction of O.sub.2 to water as a model for cytochrome-c oxidase using cofacial-bisporphyrins with relatively small internal cavities. L. M. Proniewicz et al., J. Am. Chem. Soc. (1989) 111:2105; K. Kim et al., J. Am. Chem. Soc. (1988) 110:4242. Cofacial-bisporphyrins have also been employed as models for the energy storage and electron transfer of the photosynthetic reaction center as well as for carbon monoxide and dioxygen binding affinity of hemoglobin and myoglobin. R. R. Bucks et al., J. Am. Chem. Soc. (1982) 104:340; B. Ward et al., J. Am. Chem. Soc. (198) 103:5236. The cofacial-bisporphyrins may also serve as models or substitutes for multimetal proteins such as cytochrome-c.sub.3 and nitrogenase, as well as mixed function oxidases, metallo-sandwich complexes, metal-metal multiple bonds and even anticancer drugs. T. C. Bruice in Mechanistic Principles of Enzyme Activity. pp. 227-277, J. F. Liebman et al., eds., VCH Publishers, Inc., New York (1988); R. J. Donohoe et al., J. Am. Chem. Soc. (1988) 110:6119; J. P. Collman et al., J. Am. Chem. Soc. (1990) 112:166. Advances in the synthesis of cofacial-bisporphyrins of fixed geometry will aid in the understanding of a multitude of biological and physical phenomena.
Currently used cofacial-bisporphyrin dimers are linked together by two bridges at transoid .beta.-positions of the porphyrin rings. The bridges contain amide or ester linkages that are the condensation products of acid chloride monomers with other monomers containing amine or alcohol side chains, under high dilution conditions, with yields ranging from 30-60%. These doubly-bridged molecules have a flexibility that allows the porphyrin rings to assume an undesirable offset geometry. .sup.1 H NMR studies show that in solution at room temperature, these molecules exist in a number of conformational isomers. J. P. Collman et al. in Organic Synthesis Today and Tomorrow, pp. 29-45, B. M. Trost et al., eds., Pergamon Press, Oxford (1981). Moreover, when the bridge length is decreased to four atoms or less in the doubly-bridged systems, the porphyrins are held within .pi.-.pi.-interaction distance of each other and remain rigidly eclipsed. K. Kim et al., J. Am. Chem. Soc. (1988) 110:4242.
Most cofacial-bisporphyrins also have unsubstituted meso-positions, making them susceptible to oxidation. Phenyl groups substituted at all four meso-positions of the porphyrin ring can be used to increase oxidation resistance. However, the synthesis of covalently-linked cofacial-bis-5, 10, 15, 20-tetraphenylporphyrins, ("R-(TPPH.sub.2).sub.2 s"), with relatively small internal cavities has been difficult, if not impossible. J. P. Collman et al., Proc. Natl. Acad. Sci. USA (1977) 74:18. With the exception of the elegant work of Kagan, R-(TPPH.sub.2).sub.2 s wherein the porphyrin rings are linked by four bridges and separated by less than 7 angstroms are unknown. N. E. Kagan et al., J. Am. Chem. Soc. (1977) 99:5484.
Finally, cofacial-bisporphyrins have an additional drawback when used as model enzymes: reactants can approach the metal ligands from either face of the ring system. Although interfacial access can be limited by cavity size, it has until now been difficult to control extrafacial access to the metal ligands.